Research Project
2435964
The utilization of cryopreserved allograft heart valves for transplantation in the United States is now limited by the supply of donated human hearts. The objective of the proposed studies is to help resolve this tissue valve supply problem through the continued development of a porcine valve substitute which is converted from a xenograft to an immunologically inert and stable valve bioprosthesis. This is to be achieved by ablating the antigenicity of the porcine valve by removing native cells and soluble proteins while maintaining valve viscoelasticity and ultimate tensile strength. Decellularization will be applied to both aortic and pulmonary porcine heart valves. Acellular aortic heart valves will then be modified to create a composite stentless prosthesis having only noncoronary cusps. Since cryopreserved allografts themselves become acellular in situ. is anticipated that matrices decellularized prior to implantation will have the advantage of no immunologic attack in the recipient, which is a factor which is suspected to prevent in vivo recolonization of allogeneic or xenogeneic connective tissue matrices. Limited calcification of these prostheses is expected because the pro-mineralization elements of glutaraldehyde fixation and cellular constituents are removed from the process. The potential recellularization diminished immunogenicity, and reduced calcification may each contribute to extended durability of these heart valve grafts. In the proposed studies, the consistency of the decellularization process will be established using panels of immunohistochemical markers of pig antigens, and implantation in rats. A stentless, aortic bioprosthesis composed three decellularized non-coronary aortic leaflets as well as a decellularized pulmonary porcine root will be manufactured- with assessment of the structural integrity of each design. Accelerated cyclic testing will provide pre animal testing assurance of long- term tissue wear, while a hydrodynamic performance will be measured in a pulsed flow loop. Leaflet and conduit calcification will be examined under both static in vivo and dynamic in vitro conditions. Finally, the performance of the two decellularized matrices will be demonstrated in xenogeneic in orthotopic positions in sleep. Short- term implants will demonstrate final feasibility, awhile one year implants performed under GLP conditions will provide longitudinal data on function and durability under physiologic conditions. These studies will foster development of the decellularized porcine heart valve, a unique construct which should mitigate the influences of chemical toxicity, immunogenicity, and calcification on heart value bioprosthesis durability. PROPOSED COMMERCIAL APPLICATIONS: The demand for human heart valves has exceeded the supply necessitating the postponement of surgery or the use of less desirable chemically -fixed or synthetic valves. Acellular xenogeneic heart valves mad promote in vivo recellularization of the matrix with functional cells and have diminished tendency to mineralize. Success in this effort will lead to development of a more durable, immunologically acceptable graft in virtually unlimited supply.
